Hemorrhagic shock is accompanied by a strong inflammatory reaction, the origin of which has been hypothesized in the past to be associated with specific mediators such as endotoxin, oxygen free radicals, cytokines and platelet activating factor. No conclusive evidence has been advanced that may lead to clinical utility. Instead, we have recently obtained evidence indicating that the powerful digestive enzymes, synthesized in the pancreas as part of normal digestion, may play a central role in shock and multiorgan failure. These powerful enzymes have the ability to digest almost all biological tissues. Self-digestion is prevented by compartmentalization of the fully activated enzymes in the lumen of the intestine by the mucosal epithelial barrier. In hemorrhagic shock, the mucosal barrier becomes permeable to pancreatic enzymes. The digestive enzymes enter into the wall of the intestine and initiate self-digestion of autologous submucosal extracellular matrix proteins and tissue cells, a process which leads to the production of inflammatory mediators. As an early line of defense, we hypothesize that inhibition of pancreatic enzymes in the lumen of the intestine serves to attenuate the formation of inflammatory mediators in hemorrhagic shock and consequently cell and tissue injury as well as multiorgan failure. Accordingly, we propose the following three specific aims in a porcine model of severe hemorrhagic shock: I. To examine different levels of pressure reductions and ischemic periods and their impact on the effectiveness of pancreatic enzyme inhibition to reduce the effects of inflammatory factors and improve cardiovascular function in this model; II. To examine different pancreatic enzyme inhibitors and determine optimal dosages for these enzyme inhibitors and method of delivery; and III. To evaluate the impact of intra-luminal protease inhibition in the intestine on mortality and end organ failure over 7 days after severe hemorrhagic shock. Our preliminary results indicate that blockade of digestive enzymes (serine proteases, lipases) in the lumen of the intestine provides a highly significant protection against formation of inflammatory mediators and early symptoms of multiorgan failure. The results of this research provide not only an approach to examine the different enzymatic and inflammatory processes in hemorrhagic shock but also to directly serve as the basis for possible intervention in patients.